Altered S(--)-propranolol disposition in bilateral ureter-ligated rats

Previous clinical studies indicate that the metabolic clearance of oral (+/-)-propranolol is reduced in end-stage renal failure patients. Animal models are needed to explore the mechanism(s) underlying the observed metabolic inhibition in man. The disposition kinetics of S(-)-propranolol were characterized after intravenous and peroral administration in rats with acute renal failure induced by bilateral ureteral ligation (BUL). No alteration in either the systemic clearance or the apparent volumes of distribution of S(-)-propranolol was observed in renal failure animals after a single intravenous dose of 1.5 mg/kg. In contrast, acute uremia did elicit a change in the bioavailability of orally administered S(-)-propranolol. At 36 h after ureteral ligation, the area under the serum concentration-time curve after a 6 mg/kg oral dose of S(-)-propranolol was significantly elevated in renal failure animals, which corresponded to an approximate two fold increase in its systemic availability (from 7.7 to 20.5%). Such an effect could not be demonstrated at times earlier than 36 h after ureteral ligation. Additional experiments were performed to evaluate whether concomitant changes in gastrointestinal absorption or serum protein binding of S(-)-propranolol could have contributed to the apparent increase in oral availability. The results lead to the hypothesis of an inhibited first-pass hepatic metabolism of S(-)-propranolol in acute renal failure and suggest a significant time delay in the onset of inhibition.